Therapy For Disease Research Articles

Lysosome-Targeting Protein Degradation Through Endocytosis Pathway Triggered by Polyvalent Nano-Chimera for AD Therapy.

The excessive up-regulation of receptor for advanced glycation end products (RAGE), a well-known pathological marker, drives the onset and progression of Alzheimer's disease. Although lysosome-targeting protein degradation has emerged as an effective therapeutic modality, the limited lysosome-sorting efficacy greatly hindered the degradation efficiency of target proteins. Herein, a lysosome-shuttle-like nano-chimera (endoTAC) is proposed based on polyvalent receptor binding mode for enhanced RAGE degradation as well as precise drug delivery. The endoTAC shows a high affinity to RAGE and enhances RAGE degradation due to its polyvalent-interaction with RAGE. Additionally, endoTAC features increased accumulation in diseased brain and shows promise as a precise brain delivery system. After loading with simvastatin, the SV@endoTAC proves to successfully reverse pathological features both in vitro and in vivo. The work proposes that the combination of a lysosome-targeting chimera and an effective drug delivery system can be promising in Alzheimer's disease therapy.

Visualizing sarcomere and cellular dynamics in skeletal muscle to improve cell therapies.

The giant striated muscle protein titin integrates into the developing sarcomere to form a stable myofilament system that is extended as myocytes fuse. The logistics underlying myofilament assembly and disassembly have started to emerge with the possibility to follow labeled sarcomere components. Here, we generated the mCherry knock-in at titin's Z-disk to study skeletal muscle development and remodeling. We find titin's integration into the sarcomere tightly regulated and its unexpected mobility facilitating a homogeneous distribution of titin after cell fusion - an integral part of syncytium formation and maturation of skeletal muscle. In adult mCherry-titin mice, treatment of muscle injury by implantation of titin-eGFP myoblasts reveals how myocytes integrate, fuse, and contribute to the continuous myofilament system across cell boundaries. Unlike in immature primary cells, titin proteins are retained at the proximal nucleus and do not diffuse across the whole syncytium with implications for future cell-based therapies of skeletal muscle disease.

ChiTaRS 8.0: the comprehensive database of chimeric transcripts and RNA-seq data with applications in liquid biopsy.

Gene fusions are nucleotide sequences formed due to errors in replication and transcription control. These errors, resulting from chromosomal translocation, transcriptional errors or trans-splicing, vary from cell to cell. The identification of fusions has become critical as key biomarkers for disease diagnosis and therapy in various cancers, significantly influencing modern medicine. Chimeric Transcripts and RNA-Sequencing database version 8.0 (ChiTaRS 8.0; http://biosrv.org/chitars) is a specialized repository for human chimeric transcripts, containing 47445 curated RNA transcripts and over 100000 chimeric sequences in humans. This updated database provides unique information on 1055 chimeric breakpoints derived from public datasets using chromosome conformation capture techniques (the Hi-C datasets). It also includes an expanded list of gene fusions that are potential drug targets, and chimeric breakpoints across 934 cell lines, positioning ChiTaRS 8.0 as a valuable resource for testing personalized cancer therapies. By utilizing text mining on a curated selection of disease-specific RNA-sequencing data from public datasets, as well as patient blood and plasma samples, we have identified novel chimeras-particularly in diseases such as oral squamous cell carcinoma and glioblastoma-now catalogued in ChiTaRS. Thus, ChiTaRS 8.0 serves as an enhanced fusion transcript repository that incorporates insights into the functional landscape of chimeras in cancers and other complex diseases, based on liquid biopsy results.

The Biology and Clinical Implications of PCSK7.

Discovered in 1996, PCSK7 is the seventh of the nine-membered proprotein convertase subtilisin-kexin (PCSK) family. This article reviews the various aspects of the multifaceted biology of PCSK7 and what makes it an exciting new target for metabolic dysfunction-associated steatotic liver disease (MASLD) affecting ∼30% of the population globally, dyslipidemia, cardiovascular disease (CVD), and likely cancer/metastasis. We will systematically review and discuss all the available epidemiological data, structural, cell biology, and in vivo evidence that eventually led to the discovery of PCSK7 as a novel post-translational regulator of apolipoprotein B. Interestingly, PCSK7 is the only convertase, other than PCSK9, that exhibits non-canonical/non-enzymatic functions, which will be amply described in this review. The data so far suggested that PCSK7 is a potential safe target in MASLD treatment. This was based on human epidemiological data, as well as mouse Pcsk7 knockout and mRNA translation inhibition using hepatocyte-targeted antisense oligonucleotides following a diet-induced MASLD. Additionally, of all the 9 convertases only the gene deletion of Pcsk7 and/or Pcsk9 in mice leads to healthy and fertile animals with no apparent deleterious consequences, suggesting that their pharmacological targeting is likely safe. Accordingly, the synergistic effects of inhibiting both PCSK7 and PCSK9 in a clinical setting may represent a novel therapy for various diseases. We believe that the current surge in oligonucleotide therapy, with many FDA-approved oligonucleotide-based drugs now available in the clinics, and the urgent need for novel MASLD therapeutics present an opportune moment for this timely review article.

Pharmacological Therapy (Venoactive Drugs) for Chronic Venous Disease: Effects of Micronized Purified Flavonoid Fraction

Pharmacological Therapy (Venoactive Drugs) for Chronic Venous Disease: Effects of Micronized Purified Flavonoid Fraction

A decade of real-world clinical experience with 8-week azithromycin-metronidazole combined therapy in paediatric Crohn's disease.

The aim of our study was to assess the effectiveness and side-effect profile of a combination of azithromycin and metronidazole (CD AZCRO) as alternative induction therapy for 8 weeks in mild to moderately active paediatric Crohn's disease (CD). We performed a retrospective cohort study (November 2012 to July 2023) of a regional paediatric inflammatory bowel disease service. Disease activity, faecal calprotectin (FC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), haematological parameters and albumin were collected at baseline, 8 and 16 weeks. At Week 8, patients were divided based on (paediatric Crohn's disease activity index) score and inflammatory markers (blood and stool) into: group 1 clinical remission and group 2 non-remission. A total of 48 patients were initially identified of whom 44 were included in the intention-to-treat analysis. After 8 weeks, the overall remission rate was 64%. Of the 38 patients who completed the CD AZCRO course, 28 patients (74%) entered remission (group 1) and 10 (26%) did not (group 2). At baseline a shorter disease duration, low weight z score and higher inflammatory burden (ESR, platelets and FC levels) were observed in group 2. After 8 weeks, group 1 showed improved CRP levels and higher albumin and haemoglobin levels than group 2. Median FC declined significantly from 650 mcg/g at baseline to 190 mcg/g at Week 8 in group 1 (p < 0.001). At 16 weeks, 23/28 patients (82%) continued in clinical remission. Nausea and vomiting were reported in 4/44 patients. Our real-world data demonstrate that CD AZCRO represents an alternative induction therapy for mild to moderate paediatric CD.

Early diagnosis of Alzheimer’s disease: potential of &lt;sup&gt;18&lt;/sup&gt;F-FDG PET as a biomarker of neurodegeneration

BACKGROUND: Dementia is considered one of the most actual medical problems of our time, being one of the main causes of disability among the elderly, and its prevalence will only increase in the coming years. The first place among conditions leading to dementia is given to Alzheimer’s disease (up to 70%). The effectiveness of Alzheimer’s disease therapy largely depends on the timeliness of diagnosis, which leads to the need to search for diagnostic markers that allow to detect the disease at the earliest stages. AIM: To evaluate the possibilities of using 18F-FDG PET for the early diagnosis of Alzheimer’s disease. MATERIALS AND METHODS: Cerebral metabolism was assessed using positron emission tomography with 18F-FDG. A total of 183 patients were divided into groups depending on their diagnosis and the severity of cognitive impairment. RESULTS: A characteristic pattern of cerebral metabolic disorders has been established in patients with Alzheimer’s disease. It can be detected in the early pre-dementia stages and has developmental features as the disease progresses. The pattern was characterized by bilateral hypometabolism in the parietal and temporal cortex with a predominance in its mediobasal sections. An important marker of the development of the neurodegenerative process was a metabolic disorder of the cingulate gyrus, the posterior sections of which are affected already at the earliest stages of the disease, while the involvement of its anterior sections reflects the transition to the stage of severe dementia. Described metabolic disorders prevailed in the dominant (left) brain hemisphere at all stages of the disease. CONCLUSION: Currently 18F-FDG PET can be considered the most informative of the available methods for the early diagnosis of Alzheimer’s disease which have a fairly high degree of accuracy.

Senolytic cocktail dasatinib and quercetin attenuates chronic high altitude hypoxia associated bone loss in mice

Chronic high-altitude hypoxia (CHH) induces irreversible abnormalities in various organisms. Emerging evidence indicates that CHH markedly suppresses bone mass and bone strength. Targeting senescent cells and the consequent senescence-associated secretory phenotype (SASP) with senolytics is a recently developed novel therapy for multiple age-related diseases. The combination of dasatinib and quercetin (DQ) has been proven to selectively target senescent cells and attenuate SASP in multiple tissues. In this study, experimental mice were subjected to an environment simulating 5,000 m above sea level for 8 weeks to induce CHH conditions. Our results indicated that DQ supplementation was well-tolerated with negligible toxicity. In vivo, DQ prevented reductions in BMD and BMC and improved bone microarchitecture against CHH-induced changes. Biomechanical testing demonstrated that DQ significantly improved the mechanical properties of femoral bones in CHH-exposed mice. Furthermore, DQ mitigated senescence in LepR + BMSCs and decreased the population of senescent cells, as evidenced by reduced senescence markers and SA-β-Gal staining. An analysis of serum and bone marrow aspirates showed that DQ treatment preserved angiogenic and osteogenic coupling in the bone marrow microenvironment by maintaining type H vessels and angiogenic growth factors. The results suggest that DQ has significant anti-senescence effects on BMSCs and a positive impact on the bone marrow microenvironment, supporting its clinical investigation as a therapeutic agent for CHH-related osteoporosis.

Probiotics Bi-Enzymatic Cascade Repair System for Editing the Inflammatory Microenvironment to Boost Probiotic Therapy in Inflammatory Bowel Disease.

Inflammatory bowel disease presents significant treatment challenges owing to its complex pathology. Although probiotics have shown promise as a therapeutic option, their effectiveness is often limited by low concentrations at sites of inflammation, exacerbated by excessive reactive oxygen species and inflammatory triggers. To address this, an innovative cascade repair system is developed to enhance probiotic therapeutic impact by modulating the intestinal microenvironment. This system uses iMXene's catalytic properties to neutralize reactive oxygen species in the gut and its capacity to deliver the CRISPR/dCas9 gene editing system to activate the NLR family pyrin domain containing 12 genes, helping suppress inflammation. By promoting the colonization of Lactobacillus rhamnosus, the system inhibits inflammation pathways and supports the restoration of a balanced intestinal flora through a cascade repair mechanism. These findings demonstrate significant therapeutic benefits in experimental models, with improvements in the overall well-being of treated mice and effective repair of intestinal inflammation damage. This pioneering approach holds promise for inflammatory bowel disease treatment and opens new avenues for managing other inflammatory conditions, offering valuable insights and guidance for future research into inflammatory diseases.

The Place of Topical Combined Multicomponent Drugs in the Therapy of Complicated Dermatoses (Resolution of the Expert Council)

On June 15, 2024, an expert council was held in Moscow on the topic: «The Place of Topical Combined Multicomponent Drugs in the Treatment of Complicated Dermatoses.» The council became the basis for discussing the accumulated clinical and organizational problems in the field of using multicomponent drugs in algorithms for managing patients with dermatoses of combined etiology, with concomitant visceral or cutaneous comorbidity, the influence of exposome factors on the course of steroid-sensitive, potentially complicated skin diseases. The council discussed the feasibility of prescribing multicomponent drugs in patients with altered skin microbiome against the background of dermatoses, taking into account the risk factors for the addition of a secondary infection. The prerequisites for creating a modern algorithm for the use and the place of a three-component drug produced using micronization technology, containing betamethasone, gentamicin and clotrimazole, as part of the complex therapy of chronic inflammatory itchy skin diseases were discussed.

Kopi, Trend Minuman Kekinian Dengan Banyak Manfaat Komponen Bioaktif

Coffee is a widely enjoyed beverage in Indonesia and around the world, holding a significant role as a key commodity in Indonesia's plantation sector. This beverage is popular not only for its distinctive flavor but also for its various health benefits. This article reviews several main bioactive components in coffee, including caffeine, chlorogenic acid, ferulic acid, and caffeic acid, as well as the potential health benefits of each. Caffeine is known as a stimulant that can enhance alertness, reduce drowsiness, and acts as a potential antioxidant. Chlorogenic acid functions as an anti-inflammatory, antihypertensive, antidiabetic, and anti-obesity agent, helping to reduce the risk of cardiovascular diseases. Ferulic acid has strong antioxidant effects and is used as a diabetes therapy due to its ability to reduce oxidative stress, while caffeic acid is known for its anticancer, antioxidant, and antibacterial activities, supporting the prevention of atherosclerosis and cardiovascular diseases. This article also discusses the mechanisms of action for each bioactive component within the body, particularly on the nervous system, lipid metabolism, and antioxidant activity. Through this review, coffee is understood not only as a refreshing beverage but also as a potential agent in the therapy and prevention of various chronic diseases.

Polyneuropathy and levodopa therapy in Parkinson's Disease: an evolving clinical challenge.

Polyneuropathy and levodopa therapy in Parkinson's Disease: an evolving clinical challenge.

Fine-tuning levels of filamins a and b as a specific mechanism sustaining Th2 lymphocyte functions

Augmenting the portfolio of therapeutics for type 2-driven diseases is crucial to address unmet clinical needs and to design personalized treatment schemes. An attractive therapy for such diseases would consist in targeting the recruitment of T helper 2 (Th2) lymphocytes to inflammatory sites. Herein, we show the degradation of filamins (FLN) a and b by the ASB2α E3 ubiquitin ligase as a mechanism sustaining Th2 lymphocyte functions. Low levels of FLNa and FLNb confer an elongated shape to Th2 lymphocytes associated with efficient αVβ3 integrin-dependent cell migration. Genes encoding the αVβ3 integrin and ASB2α belong to the core of Th2-specific genes. Using genetically modified mice, we find that increasing the levels of FLNa and FLNb in Th2 lymphocytes reduces airway inflammation through diminished Th2 lymphocyte recruitment in inflamed lungs. Collectively, our results highlight ASB2α and its substrates FLNa and FLNb to alter Th2 lymphocyte-mediated responses.

Revisiting microgenderome: detecting and cataloguing sexually unique and enriched species in human microbiomes

BackgroundMicrogenderome or arguably more accurately microsexome refers to studies on sexual dimorphism of human microbiomes aimed at investigating bidirectional interactions between human microbiomes, sex hormones, and immune systems. It is important because of its implications to disease susceptibility and therapy, in which men and women demonstrate divergence in many diseases especially autoimmune diseases. In a previous report [1], we presented analyses of several key ecological aspects of microgenderome by leveraging the large datasets of the HMP (human microbiome project) but failed to offer species-level composition differences such as sexually unique species (US) and enriched species (ES). Existing approaches, for such tasks, including differential species relative abundance analysis and differential network analysis, possess certain limitations given that virtually all rely on species abundance alone or are univariate, while ignoring species distribution information across samples. Obviously, it is both species abundance and distribution that shape/drive the structure and dynamics of human microbiomes, and both should be equally responsible for the universal heterogeneity of microbiomes including the sexual dimorphism.ResultsHere, we fill the gap by taking advantages of a recently developed computational algorithm, species specificity, and specificity diversity (SSD) framework (refer to the companion article) to reanalyze the HMP and complementary seminovaginal microbiome datasets. The SSD framework can randomly search and catalogue the sexually specific unique/enriched species with statistical rigor, guided by species specificity (a synthetic metric of abundance and distribution) and specificity diversity (SD). The SSD framework reveals that men seem to have more unique species than women in their gut and reproductive system microbiomes, but women seem to have more unique species than men in the airway, oral, and skin microbiomes, which is likely due to sexual dimorphism in the hormone and immune systems. We further investigate co-dependency and heterogeneity of those sexually unique/enriched species across 15 body sites, with core/periphery network analyses.ConclusionsThis study not only produced sexually unique/enriched species in the human microbiomes and analyzed their codependency and heterogeneity but also further validated the robustness of the SSD framework presented in the companion article, by performing all negative control tests based on the HMP gut microbiome samples.

Smart Healthcare Liver Segmentation Image Analysis Using AI

With an emphasis on liver segmentation in medical pictures, this research investigates the use of artificial intelligence (AI) in the field of smart healthcare. In medical image analysis, liver segmentation is a crucial task, especially for liver disease diagnosis, surgical planning, and therapy monitoring. While AI-powered approaches, particularly those that make use of deep learning, offer the potential for increases in accuracy and efficiency, traditional image analysis methods are frequently slow and prone to errors. We provide a summary of the state-of-the-art techniques, difficulties, and developments in AI-based liver segmentation, with a focus on deep learning frameworks like transfer learning and convolutional neural networks (CNNs). The goal is to demonstrate how AI has the ability to transform liver disease detection and therapy by providing intelligent medical solutions. With an emphasis on diseases including pneumonia, lung cancer, and fractures, the suggested method uses Convolutional Neural Networks (CNNs) to precisely identify anomalies and patterns. The technology improves diagnostic accuracy, decreases human error, and expedites clinical workflows by automating the diagnostic process. Furthermore, the system can get better over time by adjusting to new datasets and medical procedures because to the incorporation of continuous learning techniques. By facilitating prompt intervention and increasing diagnosis speed and accuracy, AI-based liver segmentation holds the potential to revolutionize medical practice. When handling complex liver pictures, deep learning models particularly those that make use of transfer learning and 3D segmentation networks have demonstrated greater performance, frequently attaining higher accuracy than conventional not withstanding these difficulties, recent techniques. However, addressing the inherent diversity in liver pictures resulting from variations in patient anatomy, disease development, and imaging modality (CT, MRI, Ultrasound) presents a difficulty. Developments have shown that AI models can effectively generalize to various patient populations and imaging situations when trained on sizable and varied datasets.

Bench to Any Side—The Pharmacology and Applications of Natural and Synthetic Alkylated Hydroxy Cinnamates and Cinnamides

Natural alkylated hydroxy cinnamates (AHCs) isolated from medicinal plants and the thereby designed and synthesized cinnamides are derivatives of hydroxy cinnamic acids such as p-coumaric, sinapic, ferulic, and caffeic acids, which are naturally derived from human dietary sources. The pharmacological properties displayed by AHCs based on their inherent structure range include antioxidant, antimicrobial, antiplasmodial, anti-tyrosinase, Alzheimer’s and Parkinson’s disease therapy, anticancer therapy, metabolic disease therapy, and biopesticides, which have not been reviewed together. Based on their inherent antioxidant, antimicrobial, and UV absorption and their structure–activity relationships, these cinnamyl esters and amides can be used for food preservation in emulsions and oils, as sun-protective components of skin care formulations, and in many other multifunctional applications. In conclusion, the fine-tuning of the structural features such as the type of hydroxy cinnamic acid used, the length of alkyl chains for variable lipophilicity, conversion from cinnamic to propanoic for antioxidants, the increase in methoxy or the change to amino groups to increase the molar absorption coefficient and loss of absorption values, the substitution by halides or amino groups for potent biopesticides, and conversion from esters to amide bonds leads to different AHCs for biomedical, cosmetic, and agriculture applications as an emerging field of investigation that can overall provide natural, safe, biodegradable, and sustainable molecules.

Artificial intelligence for identification of candidates for device-aided therapy in Parkinson's disease: DELIST-PD study

IntroductionIn Parkinson's Disease (PD), despite available treatments focusing on symptom alleviation, the effectiveness of conventional therapies decreases over time. This study aims to enhance the identification of candidates for device-aided therapies (DAT) using artificial intelligence (AI), addressing the need for improved treatment selection in advanced PD stages. MethodsThis national, multicenter, cross-sectional, observational study involved 1086 PD patients across Spain. Machine learning (ML) algorithms, including CatBoost, support vector machine (SVM), and logistic regression (LR), were evaluated for their ability to identify potential DAT candidates based on clinical and demographic data. ResultsThe CatBoost algorithm demonstrated superior performance in identifying DAT candidates, with an area under the curve (AUC) of 0.95, sensitivity of 0.91, and specificity of 0.88. It outperformed other ML models in balanced accuracy and negative predictive value. The model identified 23 key features as predictors for suitability for DAT, highlighting the importance of daily "off" time, doses of oral levodopa/day, and PD duration. Considering the 5-2-1 criteria, the algorithm identified a decision threshold for DAT candidates as > 4 times levodopa tablets taken daily and/or ≥1.8 h in daily “off” time. ConclusionThe study developed a highly discriminative CatBoost model for identifying PD patients candidates for DAT, potentially improving timely and accurate treatment selection. This AI approach offers a promising tool for neurologists, particularly those less experienced with DAT, to optimize referral to Movement Disorder Units.

Generation of primary feline chimeric antigen receptor T cells.

The purpose of this study was to develop procedures to engineer feline chimeric antigen receptor (CAR) T cells. 6 healthy cats were used in this study. Blood was collected, and CD3+ primary T cells were enriched by magnetic activated cell sorting, expanded, and used to generate CAR T cells. Phorbol myristate acetate plus ionomycin and concanavalin A induced similar early proliferation of CD3-enriched feline CD4+ and CD8+ T cells but phorbol myristate acetate plus ionomycin induced greater expansion over 12 days. Chimeric antigen receptor T cells were engineered by transduction with an FIV-based lentiviral system to express a human CD19 CAR. Feline CD19 CAR T cells demonstrated specific cytotoxicity against human CD19+ target cells. Conditions were developed to polarize the T cells to THelper subsets. We generated functional and specific primary feline CAR T cells and demonstrated conditions to polarize the cells, which may be therapeutically advantageous for CAR T-cell use in a variety of disease contexts. CAR T therapy has been used with great success for human hematologic malignancies and is under development for use in canines. Our study is the first demonstration of functional feline CAR T cells and describes the procedures for their engineering. These findings lay the foundation for future development of CAR T therapy for multiple feline diseases.

Quantitative Systems Pharmacology-Based Digital Twins Approach Supplements Clinical Trial Data for Enzyme Replacement Therapies in Pompe Disease.

Pompe disease is a rare, progressive neuromuscular disease caused by deficient lysosomal glycogen degradation, and includes both late-onset (LOPD) and severe infantile-onset (IOPD) phenotypes. Due to very small patient numbers in IOPD and the high phenotypic heterogeneity observed in this population, a quantitative systems pharmacology (QSP)-based "digital twin" approach was developed to perform an in silico comparison of the efficacy of avalglucosidase alfa vs. the standard of care, in a virtual population of IOPD patients. A QSP model was developed that represents key elements of Pompe disease pathophysiology, including tissue glycogen accumulation and the elevation of the biomarker urine Hex4 in both LOPD and IOPD patients. In this approach, the QSP model was used to generate digital twins of each IOPD patient enrolled in the avalglucosidase alfa clinical program, considering their respective disease burden, demographics, and treatment history. This virtual cohort supplemented clinical observations by simulating and comparing tissue glycogen and urine Hex4 following avalglucosidase alfa treatment vs. the standard of care. The digital twin analysis supports the interpretation that the enhanced reduction in urine Hex4 observed following avalglucosidase alfa treatment is attributable to greater tissue glycogen clearance. Overall, this study provides mechanism-based insight into avalglucosidase alfa efficacy across the phenotypic spectrum of Pompe disease and demonstrates the value of applying a QSP-based digital twin analysis to support rare disease drug development.

Delivery of Encapsulated Intelligent Engineered Probiotic for Inflammatory Bowel Disease Therapy.

Engineered bacterial therapy holds enormous potential for treating intestinal diseases, employing synthetic biology techniques to achieve localized drug delivery within intestines. However, effective delivery of engineered bacteria to lesion sites and ensuring sustained colonization remain challenging. Here, a mucus encapsulated microsphere gel (MM) delivery system is developed to encapsulate genetically engineered bacteria capable of detecting and treating enteritis. The MM delivery system features an external mucosal coating composed of hyaluronic acid and epigallocatechin gallate, along with internal microspheres of highly biocompatible polyserine modified alginates encapsulating with the engineered probiotics. The MM delivery system effectively protects engineered bacteria harsh environment in stomach and significantly improves intestinal adhesion of the probiotics, extending colonization up to 24h, and does not affect the entry of biomarker or release of Avcystatin. It exhibits notable diagnostic and therapeutic efficacy in inflammatory bowel disease models, thus facilitating the advancement of live biotherapeutic products toward clinical application.